General anesthesia is a drug-induced, reversible condition comprised of five behavioral states: hypnosis (loss of consciousness), amnesia (loss of memory), analgesia (loss of pain sensation), akinesia (immobility), and hemodynamic stability with control of the stress response. The mechanisms by which anesthetic drugs induce the state of general anesthesia remain one of the biggest mysteries of modern medicine. Study of the neural circuitry responsible for each of the five behavioral states of general anesthesia is a fundamental question being investigated in systems neuroscience but not for the purpose of understanding anesthesia. I propose to use systems neuroscience paradigms to establish an interdisciplinary program to solve the mystery of general anesthesia. The program will consist of a set of coordinated studies in humans, monkeys and rats using the same anesthetic agents, in addition to use of dynamical systems modeling studies of anesthetic effects on neural circuits and the development of new signal processing algorithms to track in real-time the dynamics of brain states under general anesthesia. The animal studies will use established behavioral paradigms, fMRI, and multielectrode methods to track brain activity, and microinjection and novel nanoparticle methods for site- specific delivery of anesthetic drugs. The human studies will track brain states under anesthesia using fMRI and simultaneously recorded EEG. The investigators will collaborate to integrate this information across the different systems and scales. This project will lead to a more precise, neurophysiologically-based understanding of general anesthesia, safer protocols for anesthetic drug-development, site-specific methods for anesthetic drug delivery and the design of better, neurophysiologically-based methods for measuring depth of anesthesia. Therefore, this research will improve human health by reducing the risk of anesthesia-related morbidity for patients whose surgical or medical therapies require general anesthesia. This research will also have broad impact on the training of anesthesiologists by placing greater emphasis on systems neuroscience.